SMALL MOLECULE THERAPEUTICS FOR ALZHEIMER'S DISEASE SUMMARY: Alzheimer's disease (AD) is a progressive and fatal neurological disorder that affects approximately one- tenth of the population over the age of 65. There is currently no cure for the disease. The pathological hallmarks of the disease include the formation and accumulation in the brain of -amyloid (A), widely recognized to be the major neurotoxic agent in AD and therapeutic target. Cenna has a novel technology that does not target the - or ?-secretases, which has yielded peptide drug candidates P8 and P4 with the ability to inhibit the production of A in vitro and in a Tg mouse model of AD. P4 and P8 give a strong, specific and biologically relevant binding with the purified ectodomain of human APP 695. P8 is at pre- clinical stage in its developemnt as a drug candidates for the treatment of AD. It would be a distinct advantage to identify small molecule compounds that can reduce A by the same mechanism as the peptides, by binding APP at the same sites as P4 and P8. These small molecule candidates may be developed as oral drugs that can cross the BBB. During the Phase 1 funding period we carried out molecular modeling studies to predict binding sites on APP for both P4 and P8. Having accomplished that, we virtually screened a library of e- compounds to identify those molecules that would be predicted to bind the same sites on APP as P4 and P8. Of the ~160,000 structures screened, a total of 249 suggested binding to APP at either the P4 or P8 binding site. Of those, we were able to successfully discover several candidates that could reduce both A 40 and 42 by 50-80% in an AD patient-derived induced pluripotent stem cell (ipsc) assay. In this Phase 2 application we propose to develop the best three compounds, A1, A2 and A3 further as possible orally-available disease- modifying small molecule drug candidates for the treatment of AD, that function with the same mechanism as our peptide candidates. Our Specific Aims are 1) to carry out the synthesis and evaluation in early ADME and Pharmacokinetic (PK) properties of compounds A1-A3, 2) to design and synthesize novel analogs of compounds A1-A3 and to evaluate their early ADME and PK properties and their ability to reduce A in the AD ipsc cell-based assay and 3) to study the pharmacology/efficacy of selected compounds in a transgenic mouse model of Alzheimer's disease.